Herpes simplex is a viral disease caused by herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2). HSV1 primarily causes mouth, throat, face, eye, and central nervous system infections, while HSV2 primarily causes anogenital infections. However, each may cause infections in all areas of the body. Herpes simplex virus infection causes several distinct medical disorders. Common infection of the skin or mucosa may affect the face and mouth (orofacial herpes), genitalia (genital herpes), or hands (herpes whitlow).
Herpes viruses cycle between periods of active disease, presenting as blisters containing infectious virus particle, lasts for 2-21 days, followed by a remission period, during which the sores disappear. Genital herpes, however, is often asymptomatic, though viral shedding may still occur. In all cases herpes simplex virus is never removed from the body by the immune system. Following a primary infection, the virus enters the nerves at the site of primary infection, migrates to the cell body of the neuron, and becomes latent in the ganglion, and resides as lifelong. Causes of recurrence are uncertain, though some potential triggers have been identified. Herpes simplex is most easily transmitted by direct contact with a lesion or the body fluid of an infected individual, and may also be transmitted through skin-to-skin contact during periods of asymptomatic shedding.
A cure for herpes simplex has not yet been developed. Once infected, the virus remains in the body for life. Vaccines are in clinical trials but have not demonstrated effectiveness. There is no method to eradicate herpes virus from the body, but antiviral medications can reduce viral shedding and can reduce the frequency, duration, and severity of symptomatic episodes. There are several oral antivirals that are effective for treating herpes simplex including acyclovir, valacyclovir, famciclovir, and penciclovir. Known side effects of antiviral medicines, such as Zovirax® (acyclovir) or Famvir® (famciclovir), Valtrex® (valacyclovir, include headaches, nausea, vomiting, dizziness, abdominal pain, joint pain, confusion, depression, and cardiac irregularity. Alpha-interferon has shown synergism with other anti-HSV drugs such as caffeine, trifluorothymidine, dimethyl sulfoxide, and nonoxynol-9.
Analgesics such as ibuprofen and acetaminophen have been used to reduce pain and fever. Topical anesthetic treatments such as prilocalne, lidocaine, benzocaine or tetracaine have also been used to relieve itching and pain.
Topical antiviral agents have been used to treat herpes simplex, including acyclovir, idoxuridine in dimethyl sulfoxide, and penciclovir. It has been reported that idoxuridine reduced pain duration and decreased time to loss of crust in a study. In a study, application of penciclovir cream, both early and late in the course of HSV infection, decreased the duration of lesions, pain, and viral shedding (Hamuy R. et al, Eur J. Dermatol. 1998 Jul-Aug, 8(5):310-9).
Anti-inflammatory agents, often included in the topical formulations, have been used to control the inflammatory process of herpes simplex and herpes zoster. The anti-inflammatory agents include, for example, hydrocortisone, hydrocortisone acetate and dexamethasone sodium phosphate.
Varicella zoster virus is also known as chickenpox virus, varicella virus, zoster virus, and human herpes virus type 3 (HHV-3). Primary varicella zoster virus infection results in chickenpox which generally occurs in children and young people. Even when clinical symptoms of chickenpox have resolved, varicella zoster virus remains dormant in the nervous system of the infected person (virus latency), in the trigeminal and dorsal root ganglia. In about 10-20% of cases, varicella zoster virus reactivates later in life causing herpes zoster or shingles, an illness with very different symptoms. It is reported that throughout the world the incidence rate of herpes zoster every year ranges from 1.2 to 3.4 cases per 1,000 healthy individuals, increasing to 3.9-11.8 per year per 1,000 individuals among those older than 65 years.
Herpes zoster or shingles is a viral disease. Years or decades after the initial chickenpox infection, the virus may break out of nerve cell bodies and travel down nerve axons to cause viral infection of the skin in the region of the nerve. The virus may spread from one or more ganglia along nerves of an affected segment and infect the corresponding dermatome (an area of skin supplied by one spinal nerve) causing a painful rash. The earliest symptoms of herpes zoster, including headache, fever, and malaise, are nonspecific. These symptoms are commonly followed by sensations of burning pain, itching, hyperesthesia (oversensitivity), or paresthesia (tingling, pricking, or numbness). The pain may be mild to extreme in the affected dermatome, with sensations that are often described as stinging, tingling, aching, numbing or throbbing, and can be interspersed with quick stabs of agonizing pain. In most cases, after one to two days the initial phase is followed by the appearance of the characteristic skin rash. The pain and rash most commonly occurs on the torso, resulting in a stripe or belt-like pattern that is limited to one side of the body, but can appear on the face, eyes or other parts of the body. Later, the rash becomes vesicular, forming small blisters filled with a serous exudate, as the fever and general malaise continue. The painful vesicles eventually become cloudy or darkened as they fill with blood, crust over within seven to ten days, and usually the crusts fall off and the skin heals; but sometimes, after severe blistering, scarring and discolored skin remain. Although the rash usually heals within two to four weeks, some sufferers experience residual nerve pain for months or years, a condition called postherpetic neuralgia. Herpes zoster oticus is a common complication of shingles; it is a herpes zoster virus infection of the inner, middle, and external ear. Herpes zoster oticus manifests as severe otalgia and associated cutaneous vesicular eruption, usually of the external ear canal and pinna. When associated with facial paralysis, the infection is called Ramsay Hunt syndrome or Ramsay Hunt syndrome type II.
It is until recent years, two vaccines for varicella zoster virus infection, Varivax® (varicella vaccine) for children and Zostavax® (zoster vaccine) for older adults, become available. Several oral antiviral drugs have been used to treat varicella zoster virus infection, these include acyclovir for the chicken pox, famciclovir and valaciclovir for the shingles. Antiviral drug treatment can reduce the severity and duration of herpes zoster if a seven to ten day course of these drugs is started within 72 hours of the appearance of the characteristic rash. In some countries, interferon injection has been used to treat herpes zoster in recent years, however, the side effects can be adverse, particularly among older adults. Even under potent antiviral drug treatments, often the severe pain caused by the infection is unbearable to the patients.
The macrocyclic lactones (avermectins and milbemycins) are products or chemical derivatives thereof, of soil microorganisms belonging to the genus Streptomyces. The avermectin series and milbemycin series of compounds are very potent antiparasitic agents, useful against a broad spectrum of endoparasites and ectoparasites in mammals and also having agricultural utilities against various nematode and insect parasites found in and on crops and in soil. Compounds of this group include avermectins, milbemycins, and their semi-synthetic derivatives, for example, ivermectin, doramectin, emamectin, eprinomectin, selamectin, latidectin, milbemectin, moxidectin, nemadectin, milbemycin oxime, and lepimectin. These chemicals have been described, for example, in U.S. Pat. Nos. 3,950,360, 4,199,569, 4,879,749 and 5,268,710. The avermectins and, to a lesser extent, the milbemycins, have revolutionized antiparasitic and antipest control over the past few decades.
In terms of their mechanism of action as antiparasitic agents, the avermectins block the transmittance of electrical activity in nerves and muscle cells by activating voltage dependent membrane-bound proteins containing chloride channels. Chloride channel blockers in both insects and mammals are highly toxic convulsants causing a hyperexcitation of the nervous system through antagonism of the inhibitory neurotransmitter GABA. Avermectin compounds effectively block GABA stimulated uptake and cause a release of chloride-channel dependent neurotransmitters. Milbemycin compounds have a similar mechanism of action, but a longer half-life than the avermectins. Milbemycin compounds open glutamate sensitive chloride channels in neurons and myocytes of invertebrates, leading to hyperpolarization of these cells and blocking of signal transfer.
Ivermectin has been used as an antiparasitic agent to treat various animal parasites and parasitic diseases since mid-1980's. It is commercially available for animal use as Cardomec™ (ivermectin, for felines), Zimecterin® (ivermectin, for equines) and Ivomec® (ivermectin, for bovines) by MERIAL Limited, Duluth, Ga. The medicine is available in tablets, paste, or chewables for heartworm prevention, topical solution for ear mite treatment, or as oral or injectable solution for other parasite problems. Ivermectin is also commercially available from Merck & Co., Inc for human use under the trade name of Stromectol® (ivermectin) for eradication of threadworm Strongyloides stercoralis, and for eradication of Onchocerca volvulus. The medicine is available in tablets and is orally administered by the patients. Magda et al. (Amer. J. Trop. Med. Hyg. 53(6) 1995 pp. 652-653) describe a method of topical application of ivermectin to treat head lice. U.S. Pat. No. 5,952,372 (to McDaniel) discloses a method of treating a form of rosacea associated with the ectoparasite Demodex by eliminating mites.
Recently, ivermectin has also been found useful in treating dermatological conditions. U.S. Pat. Nos. 6,133,310, 6,433,006, 6,399,652, 6,399,651 and 6,319,945 (to Parks) disclose methods of treating acne rosacea, seborrheic dermatitis, acne vulgaris, transient acantholytic dermatitis, acne miliaris necrotica, acne varioliformis, perioral dermatitis, and acneiform eruptions by topically applying an avermectin compound, particularly ivermectin, to the affected areas.
The above described parasitic diseases and dermatological conditions are not viral diseases and have different etiologies from herpes simplex virus and varicella zoster virus infections.
Herpes simplex is common public health problem. It has been reported recently that herpes simplex virus infection affects approximately 60% to 95% of adults worldwide. On the other hand, topical treatment for the painful symptoms of herpes zoster is limited. Therefore, there is a need for more effective and better topical treatments for treating herpes simplex virus and varicella zoster virus infections.